[unreadable] Although chemotherapy remains a major course of cancer treatment, it frequently fails to provide a complete cure for solid tumors. Several mechanisms contribute to this failure. Many established chemotherapeutic agents have significant antiangiogenic activity, which may reduce drug delivery during the course of a cycle of therapy. The vascular damage inflicted by the previous cycle(s) of therapy, is therefore a critically important determinant of tumor drug resistance in vivo. With our recently developed NMR techniques we can detect the delivery and spatial distribution of 13C labeled drugs in orthotopic tumors using 13C magnetic resonance techniques. We have also established that the delivery and spatial distribution of a low molecular weight contrast agent such as GdDTPA correlates well with the delivery and spatial distribution of the differentiating agent phenylbutyrate. Therefore we can now assess the efficiency of drug delivery during the course of chemotherapy in a preclinical model of human breast cancer, and evaluate the potential benefits of modulating tumor vascularization to improve tumor response to therapy with the same model genetically modified to overexpress VEGF. Our goals in this application are as follows. (i) To develop a clinically translatable surrogate marker for drug delivery by comparing tumor uptake and distribution of the carbon-13 labeled anticancer drug temozolomide and the clinically approved contrast agent GdDTPA. (ii) To determine the effect of a cycle of temozolomide chemotherapy on vascular characteristics and drug delivery. (iii) To evaluate effects of increased angiogenic capacity of tumors, genetically engineered to overexpress VEGF, on drug delivery, development of physiologic drug resistance, and treatment outcome. If successful, a clinically applicable surrogate marker would be of utmost importance for predicting effective drug delivery. Such a surrogate marker can also be used to follow strategies of improving tumor vascular delivery of chemotherapeutic agents. The experimental designs in this application will also, for the first time, evaluate the role of antivascular effects of a chemotherapeutic agent in tumor resistance using noninvasive and spatially informative techniques. [unreadable] [unreadable]